We investigate the impact of lipidation on the self-assembly of two peptide fragments from the gastrointestinal peptide hormone PYY3–36. The lipopeptides C16IKPEAP and C16IKPEAPGE contain the first 6 and 8 amino acid residues, respectively, from the PYY3–36 peptide sequence, with a palmitoyl C16 tail attached at the N-terminus. These lipopeptides form spherical micelles in aqueous solution, above a critical micelle concentration (cmc), which is pH-dependent. Modeling of small-angle X-ray scattering data along with molecular dynamics simulations shows the formation of micelles with a hydrophobic interior and a well-hydrated exterior. The lipopeptides have a disordered conformation over the pH and temperature ranges studied. The cmc is found to be independent of temperature, pointing to athermal micellization. In contrast to the presence of hydrated micelles in solution, ß-sheet amyloid fibrils form in dried samples. Thus, the nanostructure of lipidated PYY3–36 fragment peptides can be tuned by control of pH or concentration, for future applications.

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